Drechsleranol derivatives, processes for their preparation and their use

ABSTRACT

The present invention provides novel drechsleranol compounds of formula (I) which are formed by the microorganism  Drechslera australlensis , ST 003360, DSM 14093, or a fungus ST 004112, DSM 14524, during fermentation. A process for their preparation, pharmaceutical compositions containing said drechsleranols their use for the treatment and/or prophylaxis of degenerative neuropathies, such as, Alzheimeu&#39;s disease, or psychiatric disorders, such as depression, sleep disturbance or seasonal affective disorder, and their use as chelating agents or antioxidants are also disclosed and claimed.

This application claims the benefit of German priority document number10203557.1, filed Jan. 29, 2002, and U.S. Provisional Application No.60/360,363, filed Feb. 28, 2002.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel compounds called drechsleranols,which are formed by the microorganism Drechslera australlensis, ST003360, DSM 14003, or a fungus ST 004112, DSM 14524, which has not beendetermined more closely taxonomically, during fermentation, a processfor the preparation of these compounds, their use as pharmaceuticalcompositions, and their use for the treatment and/or prophyloxis ofdegenerative neuropathies, for example, Alzheimer's disease, orpsychiatric disorders, such as depression, sleep disturbances orseasonal affective disorder.

2. Description of the Art

Alzheimer's disease is a neuropsychiatric disorder which mainly occursin elderly people. The disease is manifested by a multitude of symptomswhich includes memory disorders, reduced perceptivity, orientationdisorders, speech disorders, disorders of coordinated thought, etc. InAlzheimer's patients, characteristic neurohistological changes are foundin the brain, such as, for example, deposits of “amyloid plaques” andalso a degeneration of the neurofibrils in the nerve cells (“fibrillarbundles”). These neurohistological changes are characteristic, butnonspecific, since they also occur to a smaller extent in the normalaging process.

At present no causal treatment, but only symptomatic treatment, ispossible for Alzheimer's disease. Currently available medicaments onlydelay the course of the disease, but they are not able to cure it. Thegroup consisting of the centrally active acetylcholinesterase inhibitors(Tacrin®, Donepezil®, Rivastigmin®, Galantamin®), currently offers themost important therapeutic approach, since for the memory-relevantstructures, which are impaired to a considerable extent in Alzheimer'sdisease, cholinergic signal transmission plays a great role. Thesemedicaments, however, can only be employed in the early and middlestages of the disease and they act to increase the concentration ofacetylcholine in the information-transmitting synapses of the brain. Ifthere is too severe damage to the neurons, i.e. in the late stage of thedisease, these compounds are no longer effective. Other substances whoseuse has been investigated are estrogens, nonsteroidal analgesics,antioxidants and nerve growth factors (NGF).

It is estimated that at present there are approximately one millionpeople in the Federal Republic of Germany who are suffering fromAlzheimer's disease. This figure will presumably increase still furtherin the next few years on account of the increasing life expectancy ofthe population. Novel substances for the treatment of this disorder aretherefore urgently needed.

The group consisting of the c-Jun N-terminal kinases (JNKs) are proteinkinases which are activated by oxidative stress. So far, it is knownthat only JNK-3 (in contrast to JNK-1 and JNK-2) is expressed in theneurons of the human brain. There are indications that the JNKs have aninfluence on cell death. This cell death (or apoptosis) is probably thecausal mechanism of the death of the neurons in the brain of Alzheimer'spatients (Kumagae et al., Mol. Brain Res. (1999), 67(1), 10-7). Theactivation of c-Jun N-terminal kinase is one step in this mechanism.Inhibition at this position in the biological cascade of apoptoticevents should thus prevent apoptosis, and thereby counteract thedevelopment of Alzheimer's disease and halt the progress of the disease.

A further aspect of the present invention is the treatment and/orprohylaxis of psychiatric disorder. Circadian rhythms are generated byinternal or endogenous timers (circadian clocks) which are present in apeat variety of organisms. The circadian clock is important for themaintenance of the biological rhythm. The circadian clock isself-sustaining and constant, even in total darkness, but it can besynchronized by external sign a, such as, for example, changes in thelight or the temperature. The internal clock controls is the dailyfluctuations of behavior, activity, food intake, the sleeping/walkingcycle as well as physiological changes such as, for example, hormonesecretion and change in the body temperature (Keesler at aL, Neuroreport(2000), 11(5). 951-955). Period (PER) is a central protein of thiscircadian clock, which is subject to daily variations with spec: to itsconcentration or its phosphorylation state. The phosphorylation of humanPER1 (hPER1) by the enzyme human casein kinase 1 epsilon (hCK1ε) causesa decrease in the protein stability of hPER1. Phosphorylated hPER1 has ahalf life of approximately 12 hrs, whereas unphosphorylated hPER1remains stable in cells for longer than 24 hours. Thus, modulation ofhPER1 protein is clinically of importance especially in diseases whichare associated with a disorder of the internal clock, such as, forexample, depression (Souetre E. al., Annales medico-physiologiques,1985, 143(9), 845-870). sleep disturbances or seasonal affectivedisorder. For the treatment of depression, monoamine oxidase inhibitorsand inhibitors of the reuptake of noradrenaline and/or serotonin intothe axoplasma (e.g. tricyclic antidepressants) are currently available;however, their exact mechanism of antidepressant action hitherto has notbeen clarified. With Inhibitor of hCK1ε, one would have available a nowactive principle for the treatment of psychiatric disorders, such as,for example, sleep disturbances, seasonal affective disorder and, inparticular, depression.

SUMMARY OF THE INVENTION

The invention relates to a compound of the formula (I)

wherein:

R is H, or a group of the formula —(CH(OR²))₅—CH₂—OR²;

R¹ and R² independently are H, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynylor C₆-C₁₀-aryl, wherein said C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynylor C₆-C₁₀-aryl are optionally mono- or disubstituted by —OH, ═O,—O—C₁-C₆-alkyl, —O—C₂-C₆-alkenyl, C₆-C₁₀-aryl, —NH—C₁-C₆-alkyl,—NH—C_(2-C) ₆-alkenyl, —NH₂ or halogen, wherein said —O—C₁-C₆-alkyl,—O—C₂-C₆-alkenyl, C₆-C₁₀-aryl, —NH—C₁-C₆-alkyl and —NH—C₂-C₆-alkenylsubstitutents are optionally substituted by —CN, —NH—C(O)—(C₁-C₆-alkyl)or ═NOH; or a stereoisomeric form thereof, or a pharmaceuticallyacceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

C₁-C₆-alkyl is a straight- or branched-chain alkyl having 1 to 6 Catoms, preferably having 1 to 4 C atoms, e.g. methyl, ethyl, i-propyl,tert-butyl and hexyl.

C₂-C₆-alkenyl is a straight- or branched-chain alkenyl having 2 to 6 Catoms, which is mono-, di- or triunsaturated, e.g. allyl, crotyl,1-propenyl, penta-1,3-dienyl and pentenyl.

C₂-C₆-alkynyl is a straight- or branched-chain alkynyl having 2 to 6 Catoms, which is mono- or di-unsaturated, e.g. propynyl, butynyl andpentynyl.

C₆-C₁₀-aryl is an aryl group having 6 to 10 C atoms, e.g. phenyl, benzylor 1- or 2-naphthyl, which can also be optionally substituted, forexample by halogen, such as chlorine, bromine, or fluorine, by alkylhaving 1-4 C atoms, preferably methyl, by hydroxyl, by alkoxy having 1-4C atoms, in particular methoxy, or by trifluoromethyl.

As used herein, the substituent —NH—C(O)—(C₁-C₆-alkyl) is defined as anamide wherein C₁-C₆-alkyl is a straight- or branched-chain alkyl having1 to 6 C atoms, preferably having 1 to 4 C atoms, e.g. methyl, ethyl,i-propyl, tert-butyl and hexyl.

As used herein, ‘stereoisomer’ or ‘stereoisomeric form’ is a generalterm used for all isomers of individual molecules that differ only inthe orientation of their atoms in space. The term stereoisomer includesmirror image isomers (enantiomers), mixtures of mirror image isomers(racemates, racemic mixtures), geometric (cis/trans or E/Z) isomers, andisomers of compounds with more than one chiral center that are notmirror images of one another (diastereoisomers).

As used herein, ‘R’ and ‘S’ are used as commonly used in organicchemistry to denote specific configuration of a chiral center. The term‘R’ (rectus) refers to that configuration of a chiral center with aclockwise relationship of group priorities (highest to second lowest)when viewed along the bond toward the lowest priority group. The term‘S’ (sinister) refers to that configuration of a chiral center with acounterclockwise relationship of group priorities (highest to secondlowest) when viewed along the bond toward the lowest priority group. Thepriority of groups is based upon sequence rules wherein prioritizationis first based on atomic number (in order of decreasing atomic number).A listing and discussion of priorities is contained in Stereochemistryof Organic Compounds, Ernest L. Eliel, Samuel H. Wilen and Lewis N.Mander, editors, Wiley-Interscience, John Wiley & Sons, Inc., New York,1994.

In addition to the (R)-(S) system, the older D-L system may also be usedherein to denote absolute configuration, especially with reference toamino acids. In this system a Fischer projection formula is oriented sothat the number 1 carbon of the main chain is at the top. The prefix ‘D’is used to represent the absolute configuration of the isomer in whichthe functional (determining) group is on the right side of the carbon atthe chiral center and ‘L’, that of the isomer in which it is on theleft.

As used herein, “halogen” or “halo” means fluorine, chlorine, bromineand iodine.

As used herein, ‘treat’ or ‘treating’ means any treatment, including butnot limited to, alleviating symptoms, eliminating the causation of thesymptoms either on a temporary or permanent basis, or to preventing orslowing the appearance of symptoms and progression of the named disease,disorder or condition.

As described herein, the term ‘patient’ refers to a warm blooded animalsuch as a mammal which is afflicted with a particular disease, disorderor condition. It is explicitly understood that guinea pigs, dogs, cats,rats, mice, horses, cattle, sheep, and humans are examples of animalswithin the scope of the meaning of the term.

As used herein, ‘disease’ refers to an illness, sickness or aninterruption, cessation or disorder of body functions, systems ororgans.

As used herein, ‘disorder’ refers to a disturbance of function,structure or both resulting from a genetic or embryologic failure indevelopment, or from exogenous factors such as poison, injury ordisease.

As used herein, ‘prophylaxis’ refers to the prevention of disease.

As used herein, ‘pharmaceutical carrier’ refers to known pharmaceuticalexcipients useful in formulating pharmaceutically active compounds foradministration, and which are substantially nontoxic and nonsensitizingunder conditions of use. The exact proportion of these excipients isdetermined by the solubility and chemical properties of the activecompound, the chosen route of administration as well as standardpharmaceutical practice.

As used in the examples and preparations the terms used therein shall hathe meanings indicated as follows: Me (methyl), Et (ethyl), Ph (phony!),Et₃N (triethylamine), DMF (dimethylformamide), DMSO (dimethylsulfoxide),rt (room temperature), min or mim. (minutes), h (hours), UV(ultraviolet), LC-MS (liquid chromatography mass spectrometry), t-Boc orBoc (tert-butoxycarbonyl), TFA (trifluoro acetic acid). HOAc (aceticacid), EtOAc (ethyl acetate), g (gram), mg (milligram), μg (microgram),ng (nanogram), mL (milliliter), μL (microliter), L (liter); HPLC(high-performance liquid chromatography), TLC layer chromatography); rpm(revolutions per minute), g/L (grams per liter), L/min (liters perminute), mL/min (milliliters per minute), M (molar), mM (millimolar), μM(micromolar), μCi (microCurie), CPM (counts per minute), mm(millimeter), μ (micron), nm (nanometer), ° C. (degrees Celsius), and K(Kelvin).

The invention preferably relates to a compound of the formula (I),wherein R is H or a group of the formula —(CH(OR²))₅—CH₂—OR², R¹ and R²are independently H or C₁-C₆-alkyl, or a stereoisomeric form and/or apharmaceutically acceptable salt thereof.

The invention more preferably relates to a compound of the formula (I),wherein R is a group of the formula —(CH(OR²))₅—CH₂—OR², and R¹ and R²are H, or a stereoisomeric form and/or a pharmaceutically acceptablesalt thereof. Such a compound is described by formula (II):

A further embodiment of the invention is a compound of the formula (I),wherein R and R¹ are H, or a pharmaceutically acceptable salt thereof.Such a compound is described by formula. (III):

Chiral centers in the compounds of the formulae (I) and (II) can bepresent, if not stated otherwise, in the R or in the S configuration.The invention relates both to the optically pure compounds and tomixtures of stereoisomers, such as mixtures of enantiomers and mixturesof diastereomers, in any ratio.

The invention furthermore relates to obvious chemical equivalents of thecompounds of the formula (I), (II) or (III).

Obvious chemical equivalents of the compounds according to the inventionare compounds which have the same activity as the compounds according tothe invention and exhibit a slight chemical difference or are convertedinto the compounds according to the invention under mild conditions.Obvious chemical equivalents include, for example, ethers, esters,reduction products and complexes of the compounds according to theinvention.

For example, one or more hydroxyl groups of the compounds of the formula(I), (II) or (III) can be etherified, for example with a C₁-C₆-alcoholby addition of acid, or esterified with an activated acid, for example,acid chlorides or other activated acid derivatives. It is furtherpossible, for example, for one or more double bonds of the compound ofthe formula (I), (II) or (III) to be reduced using a suitable reductant,for example, H₂/Pd.

The phenol groups of the compounds according to the invention canfurthermore form chelates with mono- or polyvalent cations. Compoundswhich contain chelate-forming phenol groups moreover have an antioxidanteffect (N. Sugihara et al., Journal of Health Science 2001, 47(2),99-106). Antioxidants (oxidation inhibitors) are organic compounds whichinhibit or prevent undesired changes in the substances to be protectedcaused by the effects of oxygen. Antioxidants are needed, for example,in plastics for protection against aging, in fats for protection againstrancidity, in oils against resinification, in aromatic substancesagainst deterioration in odor, in foodstuffs, in pharmaceuticals, etc.The action of the antioxidants is usually that they act as radicalscavengers for the free radicals occurring in the oxidation. Thecompounds of the formulae (I), (II) and (III) can therefore also be usedas chelating agents and as antioxidants.

The abovementioned methods for derivatization are described in textbookssuch as Jerry March, Advanced Organic Chemistry, John Wiley & Sons,4^(th) Edition, 1992. In order to carry out derivatization reactionsselectively, it can be advantageous to introduce suitable protectivegroups in a manner well known to one skilled in the art before thederivatization reaction. The protective groups are removed after thederivatization reaction by methods well known to one skilled in the art,and then the reaction product is purified.

The compounds of the formulae (I), (II) and (III), and the obviouschemical equivalents thereof, can be converted into the correspondingpharmaceutically acceptable salts according to methods well known to oneskilled in the art.

Pharmaceutically acceptable salts of the compounds according to theinvention are understood as meaning both inorganic and organic salts,such as are described in Remingtons Pharmaceutical Sciences (17thedition, page 1418 [1985]). Possible salts are, in particular, alkalimetal, ammonium and alkaline earth metal salts, salts withpharmaceutically acceptable amines, and salts with inorganic or organicacids such as, for example, HCl, HBr, H₂SO₄, maleic acid, and fumaricacid.

The invention additionally relates to a compound of the molecularformula C₂₆H₂₄O₉, characterized by the ¹H-NMR and ¹³C-NMR data accordingto table 2 (vide infra), or a stereoisomeric form and/or apharmaceutically acceptable salt thereof.

The invention additionally relates to a compound of the molecularformula C₂₀H₁₂O₃, characterized by the ¹H-NMR and ¹³C-NMR data accordingto table 3 (vide infra), or a pharmaceutically acceptable salt thereof.

The invention additionally relates to a compound of the formula (II),obtainable by fermentation of ST 003360 (DSM 14093) or of a variantand/or mutants of ST 003360 (DSM 14093) in a culture medium until thecompound of the formula (II) accumulates in the culture broth,subsequent isolation of the compound of the formula (II), and,optionally, conversion into a pharmaceutically acceptable salt thereof.

The invention additionally relates to a compound of the formula (III),obtainable by fermentation of ST 004112 (DSM 14524) or of a variantand/or mutants of ST 004112 (DSM 14524) in a culture medium until thecompound of the formula (III) accumulates in the culture medium,subsequent isolation of the compound of the formula (III), and,optionally, conversion into a pharmaceutically acceptable salt thereof.

The invention moreover relates to a compound of the formula (I),obtainable by fermentation of ST 003360 (DSM 14093) or of a variantand/or mutants of ST 003360 (DSM 14093) in a culture medium until thecompound of the formula (II) accumulates in the culture broth,subsequent isolation of the compound of the formula (II), orfermentation of ST 004112 (DSM 14524) or of a variant and/or mutants ofST 004112 (DSM 14524) in a culture medium until the compound of theformula (III) accumulates in the culture medium, subsequent isolation ofthe compound of the formula (III), and subsequent conversion of acompound of formula 11 or formula III into a compound of the formula(I), and, optionally, conversion into a pharmaceutically acceptable saltthereof.

An isolate of Drechslera australiensis, ST 003360, was deposited in theDeutsche Sammlung von Mikroorganismen und Zellkulturen (GermanCollection of Microorganisms and Cell Cultures) GmbH (DSM), MascheroderWeg 1B, 38124 Brunswick, Germany according to the rules of the Budapestconvention on the 28.02.2001 under the following number: DSM 14093.

The strain Drechslera australiensis, ST 003360, DSM 14093, has a darkblack-brown mycelium and has no further characteristic features.

An isolate of a hitherto taxonomically undetermined fungus, ST 004112,was deposited in the Deutsche Sammlung von Mikroorganismen undZellkulturen GmbH (DSM), Mascheroder Weg 1B, 38124 Brunswick, Germanyaccording to the rules of the Budapest convention under the followingnumber: DSM 14524.

The strain ST 004112, DSM 14524, is gray to black on malt agar. Thestrain was isolated from a soil sample from French Guyana.

The invention furthermore relates to a process for the preparation ofthe compound of formula (II), which comprises culturing themicroorganism ST 003360 (DSM 14093) or a variant and/or mutant of ST003360 (DSM 14093) in an aqueous nutrient medium, isolating andpurifying a compound of formula (II), and optionally converting it intoan obvious chemical equivalent and/or a pharmaceutically acceptable saltthereof.

The invention furthermore relates to a process for the preparation ofthe compound of formula (III), which comprises culturing themicroorganism ST 004112 (DSM 14524) or a variant and/or mutant of ST004112 (DSM 14524) in an aqueous nutrient medium, isolating andpurifying a compound of formula (III), and optionally converting it intoan obvious chemical equivalent and/or a pharmaceutically acceptable saltthereof.

The invention furthermore relates to a process for the preparation of acompound of formula (I), which comprises a) culturing the microorganismST 003360 (DSM 14093) or a variant and/or mutants of ST 003360 (DSM14093) in an aqueous culture medium, and isolating and purifying thecompound of formula (II), or culturing the microorganism ST 004112 (DSM14524) or a variant and/or mutants of ST 004112 (DSM 14524) in a culturemedium, and isolating and purifying the compound of formula (III), andb) converting a compound of formula (II) or a compound of formula (III)into a compound of formula (I), and c) optionally converting thecompound of formula (I) into a pharmaceutically acceptable salt thereof.

Instead of the strain Drechslera australiensis ST 003360, DSM 14093, orthe strain ST 004112, DSM 14524, their respective mutants and/orvariants can also be employed. A mutant is a microorganism in which oneor more genes of the genome have been modified, the gene or the genesbeing functionally and hereditarily retained which are responsible forthe capability of the organism to produce the inventive compound.

Such mutants can be produced in a manner well known to one skilled inthe art by physical means, for example irradiation, such as usingultraviolet rays or X-rays, or chemical mutagens, such as, for example,ethyl methanesulfonate (EMS); 2-hydroxy-4-methoxy-benzophenone (MOB) orN-methyl-N′-nitro-N-nitrosoguanidine (MNNG), or as described by Brock etal. in “Biology of Microorganisms”, Prentice Hall, pages 238-247 (1994).

A variant is a phenotype of the microorganism. The microorganisms havethe ability to adapt to their environment and therefore show markedphysiological flexibility. In the phenotypic adaptation, cells of themicroorganism are involved, the nature of the modification not beinggenetically conditioned and being reversible under modified conditions(H. Stolp, Microbial ecology: organisms, habitats, activities. CambridgeUniversity Press, Cambridge, GB, page 180, 1988).

The screening for mutants and variants which produce the compoundsaccording to the invention can be carried out by determination of thebiological activity of the active compound accumulated in the culturebroth, for example, by determination of the JNK-3- or hCK1ε-inhibitingaction by methods well known to one skilled in the art, or by detectionof such compounds, which are known as JNK-3- or hCK1ε-inhibitors, in thefermentation broth by, for example, HPLC or LC-MS methods that are wellknown to one skilled in the art.

The fermentation course and the formation of the compounds according tothe invention can be monitored according to methods well known to oneskilled in the art, such as, for example, by testing the biologicalactivity in bioassays or by chromatographic methods such as thin-layerchromatography (TLC) or high-performance liquid chromatography (HPLC).

In a nutrient medium which contains at least one carbon and nitrogensource and also the appropriate inorganic salts, under aerobicconditions the strain Drechslera australiensis, ST 003360, DSM 14093,produces the compound of formula (II) according to the invention, andthe strain ST 004112, DSM 14542, produces the compound of formula (III)according to the invention.

The fermentation conditions described below apply to the strainDrechslera australiensis, ST 003360, DSM 14093, and to the strain ST004112, DSM 14524.

Suitable preferred carbon sources for the aerobic fermentation areassimilable carbohydrates and sugar alcohols, such as glucose, lactose,sucrose or D-mannitol, and carbohydrate-containing natural products,such as, for example, malt extract. Suitable nitrogen-containingnutrients are amino acids, peptides and proteins and their degradationproducts, such as peptones or tryptones, furthermore meat extracts,yeast extracts, ground seeds, for example corn, wheat, beans, soy orcotton, distillation residues from alcohol production, meat meals oryeast extracts, and also ammonium salts and nitrates. Inorganic saltswhich the nutrient solution can contain are, for example, chlorides,carbonates, sulfates or phosphates of the alkali metals or alkalineearth metals, iron, zinc, cobalt and manganese. Trace elements which thenutrient solution can contain are, for example, molybdenum, copper,nickel or selenium.

The formation of the compound (II) according to the invention proceedsparticularly well in a nutrient solution which contains from about 0.1%to about 5%, preferably from about 0.5% to about 2%, of potato dextroseand from about 0.2% to about 5%, preferably from about 0.5% to about 1%,of yeast extract. The percent composition in each case is based on theweight of the entire nutrient solution.

The formation of the compound (III) according to the invention proceedsparticularly well in a nutrient solution which contains from about 0.1%to about 5%, preferably from about 0.5% to about 2%, of malt extract andfrom about 0.2% to about 5%, preferably from about 0.5% to about 1%, ofyeast extract. The percent composition in each case is based on theweight of the entire nutrient solution.

The culturing of the microorganism is carried out aerobically, i.e., forexample, submersed with shaking and stirring in shaker flasks orfermenters, optionally with introduction of air or oxygen, or on solidmedia. Culturing can be carried out over a temperature range from about18° C. to about 35° C., preferably from about 20° C. to about 30° C., inparticular from about 22° C. to about 28° C. The pH range should bebetween from about pH 4 to about pH 8, preferably between from about pH5 to about pH 6. The microorganism is cultured under these conditions,in general, over a period of from about 24 hours to about 300 hours,preferably from about 36 hours to about 168 hours.

Culturing is advantageously carried out in a number of stages, i.e., oneor more precultures are first prepared in a liquid nutrient medium,which are then inoculated into the actual production medium, the mainculture, for example in a volume ratio from about 1:10 to about 1:100.The preculture is obtained, for example, by inoculating a mycelium intoa nutrient medium and allowing it to grow from about 36 hours to about120 hours, preferably from about 48 hours to about 72 hours. Themycelium can be obtained, for example, by allowing the strain to growfrom about 3 days to about 40 days, preferably from about 4 days toabout 10 days, on a solid or liquid nutrient medium, for example,malt-yeast agar or potato dextrose agar. The invention is illustratedfurther by the following examples. Percentage compositions relate to theweight. Mixing ratios in the case of liquids relate to the volume, if noother details have been given.

The inventive compounds occur both in the mycelium and in the culturefiltrate. It is therefore expedient to separate the fermentationsolution into the culture filtrate and the mycelium by filtration and todry them separately. The dried culture filtrate and the dried myceliumare expediently separately extracted using an organic solvent, forexample methanol or propan-2-ol.

If a culture has been applied to solid medium, the inventive compoundsare present both in the mycelium and in the solid agar medium. Theentire culture is expediently lyophilized by methods well known to oneskilled in the art and the lyophilizate is extracted with an organicsolvent, for example methanol or propan-2-ol.

The extraction can be carried out over a wide pH range, but it isexpedient to work in a neutral or weakly alkaline medium, preferablybetween from about pH 7 to about pH 10. The extract can be concentratedand dried, for example, in vacuo.

One method of isolation is by separation using different polarities in amanner well known to one skilled in the art.

A further method of purification is chromatography on adsorption resinssuch as, for example, on Diaion® HP-20 (Mitsubishi Casei Corp., Tokyo),on Amberlite® XAD 7 (Rohm and Haas, USA), on Amberchrom® CG, (Toso Haas,Philadelphia, USA) or on the like. Also suitable are numerousreversed-phase supports, e.g. RP₈ and RP₁₈, such as have becomegenerally well known to one skilled in the art, for example, in thecontext of high-pressure liquid chromatography (HPLC).

A further possibility for purification of the compounds according to theinvention consists in the use of “normal-phase” chromatographicsupports, such as, for example, silica gel or Al₂O₃ or others in amanner well known to one skilled in the art.

An alternative isolation process is the use of molecular sieves, suchas, for example, Fractogel® TSK HW-40 (Merck, Germany) and others, in amanner well known to one skilled in the art. It is moreover possible torecover the compounds according to the invention from enriched materialby crystallization. Suitable solvents for this purpose are, for example,organic solvents and their mixtures, wherein the solvents may beanhydrous or water may be added. An additional process for the isolationand purification of the compounds according to the invention consists inthe use of anion exchangers, preferably in the pH range from about pH 4to about pH 10. Particularly suitable for this purpose is the use ofbuffer solutions to which portions of organic solvents have been added.

It has surprisingly been found that the compounds of formula (I)according to the invention are inhibitors of JNK-3 and CK-1. Table 1summarises the activity data of the inventive compounds by way ofexample:

TABLE 1 Activity data for the compounds of formula (II) and (III)Compound II Compound III Enzyme IC₅₀ (μM) IC₅₀ (μM) JNK-3 1.1 2.8 hCK1ε2.9 not determined

The present invention therefore also relates to the use of one or moreof the compounds of the formula (I). (II) or (Ill) according to theinvention for the treatment and/or for the prophylaxis of degenerativeneuropathies, far example Alzheimer's disease, or psychiatric disorders,for example depression, sleep disturbances or seasonal affectivedisorder.

The present invention additionally relates to a pharmaceuticalcomposition containing one or more compounds according to the invention.

Said pharmaceutical composition containing a compound of the formula(I), (II) and/or (III) is prepared by using one or more pharmaceuticallyacceptable excipients and the mixture is formed into a pharmaceuticalcomposition suitable for administration by methods well known to oneskilled in the art.

The pharmaceutical compositions according to the invention can beadministered enterally (orally), parenterally (intramuscularly orintravenously), rectally or locally (topically). Said pharmaceuticalcompositions can be administered in the form of solutions, powders,tablets, capsules including microcapsules, ointments, creams, gels orsuppositories. Possible pharmaceutically acceptable excipients forformulations of this type are the pharmaceutically acceptable liquid orsolid fillers and extenders, solvents, emulsifiers, lubricants,flavoring agents, colorants and/or buffer substances. As a suitabledose, from about 0.1 mg/kg to about 1000 mg/kg, preferably from about0.2 mg/kg to about 100 mg/kg of body weight are administered in dosageunits which contain at least the effective daily amount of the compoundsaccording to the invention, e.g. from about 30 mg to about 3000 mg,preferably from about 50 mg to about 1000 mg.

EXPERIMENTAL

The following examples are intended to serve for the illustration of theinvention in greater detail, without restricting the breadth of theinvention in any manner.

Example 1 Preparation of a Glycerol Culture of Drechslera australiensisST 003360, DSM 14093.

A sterile 300 mL Erlenmeyer flask containing 100 mL of nutrient solution(malt extract 2.0%, yeast extract 0.2%, glucose 1.0%, (NH₄)₂HPO₄ 0.05%,pH 6.0) was inoculated with the strain Drechslera australiensis, ST003360, DSM 14093, and incubated on a rotating shaker for 7 days at 25°C. and 140 rpm. A 1.5 mL sample of this culture was then diluted with2.5 mL of 50% glycerol and stored at −135° C.

Example 2 Preparation of a Main Culture in the Erlenmeyer Flask ofDrechslera australiensis, ST 003360, DSM 14093.

A sterile 300 mL Erlenmeyer flask containing 100 mL of nutrient solution(2.4 g/L of potato dextrose, 0.2 g/L of yeast extract) was inoculatedwith a culture grown in a slant tube (same nutrient solution, but with2% agar) or with 1 mL of a glycerol culture as prepared in example 1.The culture was incubated at 180 rpm and 25° C. on a shaker. The maximumproduction of the drechsleranol compound of formula (II) according tothe invention was achieved after about 144 hours. For inoculation of 10L fermenters, a 48 to 96 hour-old submersed culture (inoculation amountabout 10%) from the same nutrient solution sufficed.

Example 3 Preparation of the Compound of the Formula (II) in a 10 LFermenter

A 10 L fermenter was operated under the following conditions:

Nutrient Medium

2.4 g/L of potato dextrose

0.2 g/L of yeast extract

pH 5.1 (before sterilisation)

Incubation time: 115 hours Incubation temperature: 25° C. Stirrer speed:200 rpm Aeration: 15 L/min

It was possible to suppress foam formation by repeated addition ofethanolic polyol solution. The production maximum was achieved afterabout 96 hours to about 144 hours.

Example 4 Isolation of the Compound of Formula (II)

A fermentation batch from a glass fermenter having a nominal volume of10 L was lyophilized and extracted three times with 3 L of methanol ineach case. The methanol extract was reduced to about 500 mL in vacuo anddiluted with water to a methanol content of 10%. The diluted extract (5L) was then applied to a prepared glass column (BPG 100, 4 L internalvolume, Pharmacia Biotech), which was packed with about 0.5 liter ofMCI-Gel® CHP-20P material (adsorber resin from Mitsubishi Chemicals,Japan). The column was then eluted using a gradient of 100% water to100% acetonitrile in 60 min. The column flow (50 mL/min) was collectedin fractions (50 mL each). All fractions were tested in the JNK-3 assayand the active fractions (fractions 26-44) were combined. Concentrationin vacuo and subsequent lyophilization afforded 1.21 g of a brownpowder.

This powder was applied to a LUNA® 10μ C18 (2) column (size: 50 mm×250mm; Phenomenex, Germany) with a LUNA® 10μ C18 (2) precolumn (size: 21.2mm×60 mm) and chromatographed using a gradient of 0% to 50% acetonitrilein 0.1% ammonium acetate/water over the course of 50 minutes. The flowof the eluent was 125 mL/min, the fraction size 250 mL. Fraction 17showed the greatest activity in the bioassay. Fraction 17 waslyophilized (220 mg) and subsequently investigated by means ofanalytical HPLC and mass spectrometry which showed that the fractionconsisted of a single substance (purity>95%).

Example 5 Characterisation of the Compound of Formula (II)

The physicochemical and spectroscopic properties of the compoundisolated according to example 4 are summarised as follows:

Molecular formula: C₂₆H₂₄O₉

Molecular weight: 480

UV maxima: 226, 236, 260, 312, 340 nm

¹H- and ¹³C-NMR: see table 2

TABLE 2 ¹H- and ¹³C NMR chemical shifts δ (ppm) of the compound offormula (II) in DMSO-d₆ (TMS) at 300 K. Position ¹H (δ, ppm) ¹³C (δ,ppm) 1 — 152.57 2 — 118.06 3 7.45 129.9 (broad) 4 — 124.95 5 — 134.57 67.62 115.83 7 7.26 125.99 8 6.75 107.91 9 — 154.76 10 — 115.27 11 —152.27 12 — 119.16 13 7.38 130.13 14 7.30 117.58 15 — 135.66 16 7.28118.72 17 7.25 126.37 18 6.75 108.19 19 — 154.50 20 — 115.15 21 4.6278.4 (broad) 22 3.62 73.43 23 3.39 78.91 24 3.25 70.47 25 3.34 81.29 263.69, 3.45 61.37

Example 6 Preparation of a Glycerol Culture of ST 004112, DSM 14524

A sterile 300 mL Erlenmeyer flask containing 100 mL of nutrient solution(malt extract 2.0%, yeast extract 0.2%, glucose 1.0%, (NH₄)₂HPO₄ 0.05%,pH 6.0) was inoculated with the strain DSM 14524 and incubated on arotating shaker for 7 days at 25° C. and 140 rpm. A 1.5 mL sample ofthis culture was then diluted with 2.5 mL of 50% glycerol and stored at−135° C.

Example 7 Preparation of a Main Culture of ST 004112, DSM 14524, onSolid Medium (Plates)

Fifty sterile 25×25 cm plates were poured using 200 mL of a nutrientsolution containing 20 g/L of malt extract, 2 g/L of yeast extract and2% agar and having a pH of 7.0 in each case. The plates were inoculatedwith 2 mL of a preculture from example 6 and incubated at 25° C. Themaximum production of the compound of the formula (III) was achievedafter about 360 hours.

Example 8 Preparation of a Main Culture in the Erlenmeyer Flask of ST004112, DSM 14524

A sterile 300 mL Erlenmeyer flask containing 100 mL of nutrient solution(2.4 g/L of potato dextrose, 0.2 g/L of yeast extract) was inoculatedwith a culture grown in a slant tube (same nutrient solution, but with2% agar) or with 1 mL of a glycerol culture (see example 6) andincubated at 180 rpm and 25° C. on a shaker. The maximum production ofthe compound of the formula (III) was achieved after about 144 hours.For the inoculation of 10 L fermenters, a 48 hour- to 96 hour-oldsubmersed culture (inoculation amount about 10%) of the same nutrientsolution sufficed.

Example 9 Isolation of the Compound of Formula (III)

Fifty plate cultures (20×20 cm each plate) were lyophilized andextracted twice with 10 L of methanol in each case. The methanol extractwas reduced to about 500 mL in vacuo and diluted to a methanol contentof 10% with water. The diluted extract (5 L) was then applied to aprepared glass column (BPG 100, 4 L internal volume, Pharmacia Biotech),which was packed with about 0.5 liter of MCI-Gel® CHP-20P material(adsorber resin of Mitsubishi Chemicals, Japan). The column was elutedusing a gradient of 100% water to 100% acetonitrile over 30 min. Thecolumn flow (50 mL/min) was collected in fractions (50 mL each). Allfractions were tested in the JNK-3 assay and the active fractions(fractions 30-44) were combined. Concentration in vacuo and subsequentlyophilization afforded a brown gummy residue.

The residue was dissolved in water/acetonitrile (1:1), centrifuged andapplied to a LUNA® 10 μC18 (2) column (size: 21 mm×250 mm; Phenomenex,Germany) and chromatographed using a gradient of 0% to 100% acetonitrilein 0.1% ammonium acetate/water over the course of 60 minutes. The flowof the eluent was 33 mL/min the fraction size 33 mL. Fractions 28-32showed the greatest activity in the bioassay. Fractions 28-32 werelyophilized and then further purified. For this, the substance waschromatographed on a LUNA® 5 μC18 (2) column (size: 10 mm×250 mm;Phenomenex, Germany) using a gradient of 30% to 60% acetonitrile in 0.1%ammonium acetate/water over the course of 45 minutes. The flow of theeluent was 6.5 mL/min, and the fraction size was 6.5 mL. Fractions 18-24showed the greatest activity in the bioassay. After freeze-drying(yield: 10 mg), subsequent analysis by means of analytical HPLC and MSspectrometry showed that the material was a homogeneous compound(purity>95%).

Example 10 Characterisation of the Compound of Formula (III)

The physicochemical and spectroscopic properties of the compoundisolated according to example 9 can be summarised as follows:

Molecular formula: C₂₀H₁₂O₃

Molecular weight: 300

UV maxima: 226, 236, 260, 312, 340 nm

¹H- and ¹³C-NMR: see table 3

TABLE 3 ¹H- and ¹³C NMR chemical shifts δ (ppm) of the compound offormula (III) in CD₃OD (TMS) at 300 K. Position ¹H (δ, ppm) ¹³C (δ, ppm)1 — ˜154.3 (a) 2 — ˜121.3 (a) 3 7.46 130.63 4 7.31 119.55 5 — 137.60 67.24 119.55 7 7.22 127.52 8 6.69 109.20 9 — ˜157.0 10 — ˜117.5 (a) (a)For these carbon atoms, no (or an extremely broad) signal is observed inthe ¹³C spectrum. The chemical shifts were therefore determined by meansof correlations in the Heteronuclear Multi-Bond Connectivity (HMBC)spectrum.

Example 11 Activity of the Compounds of Formulae (II) and (III) in theJNK-3 Assay

The assay is carried out on a CyBio pipetter system in a 384-hole plateformat. The assay contains 10 μL of sample (extract or pure substance,for example a compound of formula (II) or of formula (III)) in 3% DMSO,10 μL of an enzyme/substrate mixture (JNK-3/GST-ATF2) and 10 μL of ATPin a final volume of 30 μL. After incubation at 37° C. for 20 minutes,50 μL of the HTRF antibody mixture (XL665-anti-GST/(Eu)cryptateanti-P-ATF2) are added. After 120 minutes at room temperature, thesignal emission of the energy transfer and of europium at 665 and 615 nmis measured after the samples have been stimulated at 340 nm in aVictor² (WALLAC).

Buffer I for the Dilution of JNK3, GST-ATF2, ATP:

25 mM HEPES, pH 7.5 100 μM MgCl₂ 0.03% TRITON X 100 10 mM DTT 5%Glycerol

Buffer II for the Dilution of the HTRF Reagents:

100 mM HEPES, pH 7.0 100 mM KF 133 mM EDTA 1 g/L BSA

Reagents: Supplier: Final concentration: JNK3 Kinase Biotech, Vitry 8ng/well GST-ATF2 Biotech, Vitry 88 ng/well ATP Sigma, A7699 15 μMAnti-GST-XL665 CisBio 125 ng/well Anti-P-ATF2-(Eu)cryptate NEB/CisBio 6ng/well

Each plate contains 16 positive controls (maximum energy transfer,buffer I instead of samples), 8 blank controls (minimum energy transfer,buffer II instead of ATP) and 8 holes which contain EDTA 200 μM.

The results are calculated as follows:

Firstly, the signal ratio=(intensity (665 nm)/intensity (615 nm)) isdetermined. A blank correction is then made using the following formula:

delta F(%)=[(ratio (sample)−ratio(minimum))/(ratio (minimum))]×100

The activity of the samples is then calculated in the following manner:

Inhibition (%)=100×[1−(delta F(sample)/delta F(maximum))]

Example 12 Activity of the Compound of Formula (II) in the hCK1ε Assay

The assay is carried out in a Jobi-Well (CyBio) and Biomek 2000 pipettersystem in the 384-hole plate format. The 384-hole plates are coated with50 μL per well of a casein solution of the concentration 100 μg/mL incoating buffer (corresponds to 5 μg of casein per well, casein Sigma)and stored overnight at 4° C. Washing four times with 90 μL of washsolution 1 (50 mM HEPES pH 7.4 and 150 mM NaCl) is then carried out. Thereaction is carried out in a final volume of 50 μL. During the course ofthis, 10 μL of dilute natural substance extract in each case, forexample a compound of formula (II) or a compound of formula (III), 20 μLof hCK1ε enzyme solution (corresponds to 29 ng of casein per well) and20 μL of ATP solution (final concentration: 0.4 μCi of ³³P-γ-ATPradiolabeled (“hot”) and 0.4 μM of cold ATP per well) are pipetted ontothe coated plates. The plates are then incubated at 37° C. for one hour.The plates are then washed four times with 75 μL of wash solution 2(phosphoric acid, 3%) and measured for 30 seconds in a MicroBeta Triluxcounter (WALLAC).

hCK1ε Enzyme Solution: 1.45 μg of Recombinant hCK1ε per mL of KinaseBuffer

Kinase Buffer

50 M HEPES pH 7.4

10 mM MgCl₂

0.25 mM DTT

0.6 mM EGTA

Coating Buffer:

27.5 mM Na₂CO₃

22.5 mM NaHCO₃ (pH 9.6)

in 0.9% NaCl

ATP Solution: 20 μCi/mL of ³³P-γ-ATP and 1 μM of Cold ATP

On each plate, 16 holes are used in order to determine the total enzymeactivity (without inhibitor addition) and a further 16 holes withoutenzyme addition in order to determine the nonspecific reaction.

The inhibition of a sample can be calculated according to the followingformula:

[1−(CPM(sample)−CPM(nonspec.))/(CPM(enzymeconcentration)−CPM(nonspec.))]×100(%)

The results of the JNK-3 and hCK1ε assays are summarized in table 1(vide supra).

What is claimed is:
 1. A compound of formula (I)

wherein: R is H, or a group of the formula —(CH(OR²))₅—CH₂—OR²; R¹ andR² independently are H, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkenyl orC_(6-C) ₁₀-aryl, wherein said C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynylor C₆-C₁₀-aryl are optionally mono- or disubstituted by —OH, ═O,—O—C₁-C₆-alkyl, —O—C₂-C₆-alkenyl, C₆-C₁₀-aryl, —NH—C₁—C₆-alkyl,—NH—C₂-C₆-alkenyl, —NH₂ or halogen, wherein said —O—C₁—C₆-alkyl,—O—C₂-C₆-alkenyl, C₆-C₁₀ aryl, —NH—C₁-C₆-alkyl and —NH—C₂-C₆-alkenylsubstituents are optionally substituted by —CN, —NH—C(O)—(C₁-C₆-alkyl)or ═NOH; or a stereoisomeric form thereof, or a pharmaceuticallyacceptable salt thereof. 2.The compound according to claim 1 wherein R¹and R² independently are H or C₁-C₆-alkyl.
 3. The compound according toclaim 2 of formula (II)

or a stereoisomeric form thereof, or a pharmaceutically acceptable saltthereof.
 4. The compound of formula (II) according to claim 3 having¹H-NMR spectrum peaks at about 3.25. 3.34, 3.39, 3.45, 3.62, 3.69, 4.62,6.75, 6.75, 7.25, 7.26, 7.28, 7.30, 7.38, 7.45, 7.62 ppm and ¹³C-NMRspectrum peaks at about 61.37, 70.47, 73.43, 78.4 (broad), 78.91, 81.29,107,91, 108.19, 115.15, 115.27, 115.83, 117.58, 118.06, 118.72, 119.16,124.95, 125.99, 126.37, 129.9 (broad), 130.13, 134.57, 135.66, 152.27,152.57, 154.50, 154.76 ppm.
 5. The compound according to claim 2 offormula (III)

having ¹H-NMR spectrum peaks at about 6.69, 7.22, 7.24, 7.31 7.46 ppmand ¹³C-NMR spectrum peaks at about 109.20, 117.5, 119.55, 119.55,121.3, 127.52, 130.63, 137.60, 154.3, 157.0 ppm, or a pharmaceuticallyacceptable salt thereof.
 6. A process for the preparation of thecompound of formula (I) as set forth in claim 1 comprising the steps ofa) culturing the microorganism ST 003360 (DSM 14093) or a variant and/ormutants of ST 003360 (DSM 14093) in a culture medium, and isolating andpurifying the compound of the formula (II), or culturing themicroorganism ST 004112 (DSM 14524 or a variant and/or mutants of ST004112 (DSM 14524) in a culture medium, and isolating and purifying thecompound of the formula (III), b) converting the compound of formula(II) or the compound of formula (III) into the compound of formula (I),and c) optionally converting the compound of formula (I) into apharmaceutically acceptable salt.
 7. The compound of formula (I)produced by the process of claim
 6. 8. A process for the preparation ofthe compound of formula (II) according to claim 3 comprising the stepsof a) culturing the microorganism ST 003360 (DSM 14093 or a variantand/or mutant of ST 003360 (DSM 14093), b) isolating and purifying thecompound of formula (II), and c) optionally converting the compound offormula (II) into a chemical equivalent or a pharmaceutically acceptablesalt.
 9. The compound of formula (II) produced by the process of claim8.
 10. A process for the preparation of the compound of formula (III)according to claim 5 comprising the steps of a) culturing themicroorganism ST 004112 (DSM 14524 or a variant and/or mutant of ST004112 (DSM 14524), b) isolating and purifying the compound of formula(III), and c) optionally converting the compound of formula (III) in achemical equivalent or a pharmaceutically acceptable salt.
 11. Thecompound of formula (III) produced the process of claim
 10. 12. Apharmaceutical composition having JNK-3 inhibitory activity comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound of formula (I)

wherein: R is H, or a group of the formula —(CH(OR²))₅—CH₂—OR²; R¹ andR² independently are H, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl orC_(6-C) ₁₀-aryl, wherein said C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynylor C₆-C₁₀-aryl are optionally mono- or disubstituted by —OH, ═O—,O—C₁-C₆-alkyl, —O—C₂-C₆-alkenyl, C₆-C₁₀-aryl, —NH—C₁-C₆-alkyl,—NH—C₂-C₆-alkenyl, —NH₂ or halogen, wherein said —O—C₁-C₆-alkyl,—O—C₂-C₂-C₆-alkenyl, C₆-C₁₀-aryl, —NH—C₁-C₆-arkyl and —NH—C₂-C₆-alkenylsubstituents are optionally substituted by —CN, —NH—C(O)—(C₁-C₆-alkyl)or ═NOH; or a stereoisomeric form thereof, or a pharmaceuticallyacceptable salt thereof.
 13. A pharmaceutical composition having hCK1εinhibitory activity comprising a pharmaceutically acceptable carrier anda therapeutically effective amount of a compound of formula (I)

wherein: R is H, or a group of the formula —(CH(OR²))₅—CH₂—OR²; R¹ andR² independently are H, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl orC₆-C₁₀-aryl, wherein said C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl orC₆-C₁₀-aryl are optionally mono- or disubstituted by —OH, ═O,—O—C₁-C₆-alkyl, —O—C₂-C₆-alkenyl, C₆-C₁₀-aryl, —NH—C₁—C₆-alkyl,—NH—C₂-C₆-alkenyl, —NH₂or halogen, wherein said —O—C₁-C₆-alkyl,—O—C₂-C₆-alkenyl, C₆-C₁₀aryl, —NH—C₁-C₆-alkyl and —NH—C₂-C₆-alkenylsubstituents are optionally substituted by —CN, —NH—C(O)—(C₁-C₆-alkyl)or ═NOH; or a stereoisomeric form thereof, or a pharmaceuticallyacceptable salt thereof.
 14. A method of inhibiting JNK-3 activity totreat a degenerative neuropathy which comprises administering to apatient in need of said treatment a therapeutically effective amount ofa compound of formula (I):

wherein: R is H, or a group of the formula —(CH(OR²))₅—CH₂—OR²; R¹ andR² independently are H, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl orC₆-C₁₀-aryl, wherein said C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl orC₆-C₁₀-aryl are optionally mono- or disubstituted by —OH, ═O,—O—C_(1 -C) ₆-alkyl —O—C₂-C₆-alkenyl, C₆-C₁₀-aryl, —NH—C₁-C₆-alkyl,—NH—C₂-C₆-alkenyl, —NH₂ or halogen, wherein said —O—C₁-C₆-alkyl,—O—C₂-C₆-alkenyl, C₆-C₁₀-aryl, —NH—C₁-C₆-alkyl and —NH—C₂-C₆-alkenylsubstituents are optionally substituted by —CN, —NH—C(O)—(C₁-C₆-alkyl)or ═NOH; or a stereoisomeric form thereof, or a pharmaceuticallyacceptable salt thereof.
 15. The method according to claim 14 whereinthe degenerative neuropathy is Alzheimer's disease.
 16. A method ofinhibiting hCK1ε activity to treat a psychiatric disorder whichcomprises administering to patient in need of said treatment atherapeutically effective amount of a compound of formula (I):

wherein: R is H, or a group of the formula —(CH(OR²))₅—CH₂—OR²; R¹ andR² independently are H, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl orC_(6-C) ₁₀-aryl, wherein said C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynylor C₆-C₁₀-aryl are optionally mono- or disubstituted by —OH, ═O,—O—C₁-C₆-alkyl, —O—C₂-C₆-alkenyl, C₆-C₁₀-aryl, —NH—C₁-C₆-alkyl,—NH—C₂-C₆-alkenyl, —NH ₂ or halogen, wherein said —O—C₁-C₆-alkyl,—O—C₂-C₆-alkenyl, C₆-C₁₀-aryl, —NH —C₁-C₆-alkyl and —NH—C₂-C₆-alkenylsubstituents are optionally substituted by —CN, —NH—C(O)—(C₁-C₆-alkyl)or ═NOH; or a stereoisomeric form thereof, or a pharmaceuticallyacceptable salt thereof.
 17. The method according to claim 16 whereinthe psychiatric disorder is depression, sleep disturbances or seasonalaffective disorder.
 18. An antioxidant composition comprising aneffective amount of a compound as set forth in claim
 1. 19. A mono- orpolyvalent cation chelate forming composition comprising an effectiveamount of a compound as set forth in claim 1.